Abstract
Interleukin-2 (IL-2) regulates key aspects of CD8 T cell biology–signaling through distinct pathways IL-2 triggers critical metabolic and transcriptional changes that lead to a spectrum of physiological outcomes such as cell survival, proliferation, and effector differentiation. In addition to driving effector differentiation, IL-2 signals are also critical for formation of long-lived CD8 T cell memory. This review discusses a model of rheostatic control of CD8 T cell effector and memory differentiation by IL-2, wherein the timing, duration, dose, and source of IL-2 signals are considered in fine-tuning the balance of key transcriptional regulators of cell fate.
Highlights
Interleukin-2 (IL-2)–the first cytokine to be identified and characterized more than three decades ago—has emerged as a pleiotropic player in a variety of seemingly paradoxical immune functions
We have previously shown that memory-fated effector CD8 T cells selectively retain the ability for robust IL-2 production in response to antigenic stimulation compared to their terminally differentiated effector counterparts [8, 15, 16, 44]
Alternatively—owing to its ability to induce proliferation and effector differentiation–strong and sustained IL-2 signals might be employed for immunotherapeutic interventions against cancers and chronic infections that rely on activation of a large pool of antigen-specific CD8 T cells
Summary
Interleukin-2 (IL-2)–the first cytokine to be identified and characterized more than three decades ago—has emerged as a pleiotropic player in a variety of seemingly paradoxical immune functions. Proinflammatory cytokine signals such as IL-12, IFN-γ, and type-1 interferons (IFN-α/β)—commonly referred to as signal 3 for their role in promoting optimal clonal expansion of effector CD8 T cells—are believed to complement IL-2, possibly non-redundantly [43, 44] Such collaboration, between IL-12 and IL-2 has been recently shown to be important for optimal expression of transcription factors Tbet and Blimp-1, which synergize to drive a terminal effector differentiation program in CD8 T cells [45]. Consistent with the pro-proliferative role of IL-2, terminally differentiated effector CD8 T cells (SLECs) that express IL-2Rα for longer duration during an acute infection expand more than their memory-fated counterparts (MPECs) that downregulate the expression of IL2Rα earlier [15, 16, 50,51,52] Together, these findings support the notion that metered IL-2 signals are required for optimal protective immunity and present a model of rheostatic control of CD8 T cell fates by IL-2 during acute infections. How effector and memory CD8 T cell fates are defined in vivo through differential metabolic programming by varying IL-2 strength or duration remains to be elucidated
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